1. Carotid Trials in Progress and Predictions on Outcomes
Kenneth Rosenfield, MD, FACC, FAHA
Section Head, Vascular Medicine and Intervention
Massachusetts General Hospital
Boston, Massachusetts, U.S.A.

2. Kenneth Rosenfield, MD Conflicts of Interest
Consultant
Abbott Vascular
Baxter
Harvard Clinical Research Institute
Micell
Complete Conference Management
Vortex
Endospan
Equity
Icon
CardioMEMs
Medical Simulation Corporation
Primacea
Research or Fellowship Support
Abbott Vascular
Cordis
Lutonix/Bard
Boston Scientific
Baxter
Atrium
IDEV
Board Member
VIVA Physicians

3. Carotid Trials – Where have we come from?

4. Stroke Prevention by Intervention Summary of what evidence we have…
RCT’s: CEA vs. OMT
completed*
Symptomatic
High-risk
Asymptomatic
High-risk
None
None
Symptomatic
Standard-risk
Asymptomatic
Standard-risk
NASCET
ACAS
VA Trial
ECST
ACST 1

5. Benefit of medical Rx with revascularization over Med Rx alone
ACST - Early vs. Deferred Carotid Endarterectomy in Asymptomatic Patients with ICA Stenosis
Any Stroke or Perioperative Death
Time (years) 
Benefit of medical Rx with revascularization over Med Rx alone
ACST Investigators. Lancet 2004;363:

6. RCT’s: CAS vs. OMT for stroke prevention
Symptomatic
High-risk
Asymptomatic
High-risk
None
None
Symptomatic
Standard-risk
Asymptomatic
Standard-risk
None
None
In absence of “head to head” trials vs. OMT, can only infer ability of CAS to prevent stroke based on:
a) registry studies of CAS and
b) RCT’s comparing it to CEA!

7. Carotid Artery Disease RCT’s: CAS vs. CEA
completed*
SAPPHIRE *
ongoing
Symptomatic
High-risk
Asymptomatic
High-risk
None
None
KENTUCKY *
Symptomatic
Standard-risk
Asymptomatic
Standard-risk
EVA3s, SPACE 1 *
ACT1, SPACE2, ACST2
CREST

8. We should have refused more patients!
SAPPHIRE
>50% Stenosis Sx
80% Stenosis Asx
One or More Comorbidity Conditions
Physician Team: Neurologist, Surgeon, Interventionalist
CONSENSUS: pts enrolled
RANDOMIZED
334
SURGICAL
REFUSAL
INTERVENTIONAL
REFUSAL
TREATED
310
Stent Registry n=409
Surgical Registry n=7
We should have refused more patients!
CEA n=151
STENT n=159

9. SAPPHIRE Trial: 1-Year Outcome - sxatic and asxatic high surgical risk patients
20.1%
p=0.048
12.0% 30 25 20 15 10 60 90
120
150
180
210
240
270
300
330
360
Time after Initial Procedure (days)
Cumulative Percentage of MAE
Nitinol
Stent
Carotid Endarterectomy 5
In high risk patients, carotid stenting with distal embolic prevention is associated with fewer deaths, myocardial infarctions or strokes at 30 days than carotid endarterectomy, and these differences persist at 1 year.

10. SAPPHIRE 3-Year Outcomes
Freedom from MAE
N Engl J Med 2008;358:1572-9

11. 30 Day Event Rates (2000--->2008)
All Stroke - Stenting Trials for High Risk Surgical Patients
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Factors: embolic protection, experience, case selection 11

12. Protect  Stroke and Death 1.8%

13. Carotid Disease - Natural History Unanswered Questions
Effect of...
Sxatic status
Degree of narrowing
Morphology and consistency
Location
Patient substrate – standard or high surgical risk patient
Clinical consequences
Benign or not (stroke, MI, death)

14. Carotid Disease - Revascularization Unanswered Questions
Effect of...
Patient substrate
Standard or high surgical risk patient
Sxatic status
Age
Lesion status
Degree of narrowing
Location
Morphology and consistency

15. Carotid Revascularization Unanswered Questions
Optimal lesion characterization
Severity
DUS
CTA
MRA
Angiography
Embolic potential (risk stratification)
DWI
Plaque characterization (e.g. ulceration)
Biological plaque imaging

16. Carotid Revascularization Unanswered Questions
Selection of optimal revascularization modality
CEA
Stenting

17. Carotid Stenting Unanswered Questions
Equipment
Embolic protection
Proximal
Distal
Stent
Closed-cell
Open-cell
Covered or “meshed”
Access site
Femoral
Upper extremity
Direct carotid - cutdown or puncture

18. Carotid Disease Adding to the evidence base…
Randomized Controlled Trials in Progress
SPACE 2
ACST 2
ACT 1
Randomized Controlled Trials Planned
CREST 2
Single Arm Trials and Registries
NCDR CARE and SVS
Gore and MDT Prox protection

20. SPACE 2 – “Stent-protected angioplasty in Asymptomatic Carotid Artery Stenosis”
Funding – German Research Council
Start date – original 1/07; revised 11/09
Countries – Austria, Germany, Switzerland
Hypothesis
Superiority of revasc (CAS or CEA) c/t OMT
CAS not inferior to CEA
Primary Outcome
Death or any stroke w/n 30 days
Ipsilat stroke within 5 yrs.
Design – RCT – three open arms
OMT
OMT plus CAS
OMT plus CEA
Inclusion
<86 y.o.; 6 mos w/o sx’s

21. SPACE 2
Asymptomatic (no ipsilateral symptoms within previous 180 days)
Carotid artery stenosis
>/=
70%
Ultrasound
proven by certified study personal
Informed consent
Randomisation
CEA
CAS
conservative
n=1550
n=1550
n=540
Procedure
within 30 days
Procedure
within 30 days
Optimal medical treatment up to 5 years

22. SPACE 2 – “Stent-protected angioplasty in Asymptomatic Carotid Artery Stenosis”
Progress
# Pts to be randomized patients
Currently – <300 (after two years)
Randomization scheme altered to:
Asx patient <86 y.o.
Asx patient <86 y.o.
From:
To: * *
CAS
CEA
Best Medical Tx
Revasc- either
CEA or CAS
Best Medical Tx

23. The HTA/BUPA Foundation ACST-2
A large simple randomised trial of CEA (carotid endarterectomy) vs CAS (carotid stenting) for the prevention of stroke
Aims to randomise patients with asymptomatic carotid stenosis in whom intervention is thought to be clearly needed, but where there is substantial uncertainty as to which procedure is best

24. ACST-2
Subjects in whom CEA and CAS are anatomically suitable are randomized 1:1 to CEA or CAS.
The main outcomes are 1-month stroke/MI/death and long term stroke (5 or more years).
Randomization and 1-month evaluations are performed by the study doctor, and long term follow up is primarily though direct contact from the ACST office.

25. Asymptomatic Carotid Stenosis Trial (ACST-2) Randomisation to Stenting or Surgery
Funded to Plans
200 centres to randomise at least 5000 patients
Experience with more devices, longer follow up, determine groups who may/ may not benefit
Since randomisation started (2 years)
45 Centres (16 countries) have entered patients
127 centres have joined or are joining

26. 16 Countries Randomising in ACST-2
Belgium
Czech Republic
France
Germany
Greece
Ireland
Israel
Italy
Netherlands
Norway
Poland
Serbia
Slovenia
Spain
Sweden
United Kingdom

27. ACST-2 UK 25 centres (Mar 2010) Centre open Joining Belfast
Newcastle Hospitals
Joining
Sunderland Royal Infirmary
James Cook Hospital
Royal Preston Hospital
Univ Hospital North Durham
Bishop Auckland General Hospital
Univ Hospital of South Manchester
Manchester Royal Infirmary
Hull Royal Infirmary
Sheffield Vascular Institute
Norfolk and Norwich Univ Hospital
Queens Medical Centre, Nottingham
Addenbrookes Hospital
Southend
Univ Hospital of North Staffordshire
St Mary’s London
Sandwell and West Birmingham
St Georges, London
East Kent and Canterbury
Bristol Royal Infirmary
Belfast
Bournemouth
Royal Sussex, Brighton

28. Centre Recruitment
125 62
Mar
2010

29. CREST 2 950 patients at ~70 centers
Power ~90% to detect 4.8% treatment difference (1.2% per year)
Primary Endpt – Composite of stroke or death within 30 days or ipsilat stroke up to 4 years
SAMMPRIS – style Intensive medical management
Criteria
>35 y.o.; asymptomatic for 180 days
>70% stenosis (det by DUS, CAT, MRA, CBA)
Series of exclusion criteria each for CEA and CAS

39. Asymptomatic Carotid stenosis, stenting versus endarterectomy Trial
Carotid stenting is not currently approved by the FDA for asymptomatic patients who are at standard risk for surgery.
CAUTION: Investigational device. Limited by Federal (or United States) law to investigational use.
Confidential: This information is confidential and is intended for distribution to ACT I Study Site participants ONLY. This document contains Abbott Laboratories and Abbott Vascular proprietary information and shall not be duplicated, disclosed to others, or used for purposes other than to carry out the intent for which this material is delivered.
©2008
VIVA 2008 ( Las Vegas, NV)
September 22nd 2008
AP Rev A 39

40. Summary - ACT 1 Focus only on asymptomatic patients
excludes high risk for CEA--protocol defined
excludes high risk for CAS--protocol defined
surgeon and interventionalist criteria are strict and verified (IMC and SMC)
Independent neuro assessment
embolic protection required
central core labs, independent audit

41. ACT I: Study Design Prospective, randomized, 2-arm, multicenter trial
3:1 randomization CAS to CEA
Lead-in enrollment of up to 400 subjects
Maximum of 1658 pivotal subjects
Followed at 1, 6, 12 months & annually for 5 yrs
Contemporary medical therapy for all patients
VIVA 2007 ( Las Vegas, NV)
September 25th 2007

42. Key Inclusion Criteria
• Subject > 18 and  80 years of age.
• Subject asymptomatic
no stroke or TIA (hemispheric or ocular) within 180 days prior to procedure
neurologist must confirm status
Carotid stenosis >70% and <99% by carotid duplex (accredited lab) or angiography (visual estimate)

43. Key Exclusion Criteria Clinical
• Bilateral significant carotid stenosis (contralateral stenosis > 60% by duplex or angiography)
• High risk surgical candidate
• Known cardiac sources of emboli

44. Primary Endpoint Composite
• Any stroke*, myocardial infarction and death during 30-day post procedural period
Ipsilateral stroke* between 31 and 365 days post procedure
*Independent neurologic assessment

45. Summary - ACT 1
ACT 1 will focus on evaluating CAS in asymptomatic patients
excludes high risk for CEA--protocol defined
excludes high risk for CAS--protocol defined
surgeon and interventionalist criteria are strict and verified
standardized protocol: embolic protection
central corelabs, independent audit

46. ACT 1 - Enrolling Sites as of September 2008
Dartmouth
Massachusetts General Hospital
St. Francis, NY
St. Luke’s Milwaukee
Deaconess Medical Center
University of Rochester
William Beaumont Hospital
NYU Medical Center
Albany Medical Center
Oregon Health & Science University
Rush University Medical Center
Lenox Hill Hospital
Our Lady of Lourdes
St. John’s Hospital / Prairie Medical
Columbia Presbyterian
Millard Fillmore Hospital
North Central Heart Institute
Detroit Medical Center
Hospital of Univ. of Pennsylvania
Allegheny General Hospital
Washington Hospital Center
El Camino Hospital
Northwestern University Memorial Hospital
Cleveland Clinic Foundation
Riverside Methodist Hospital
Harrisburg Hospital / Pinnacle Health
Hoag Memorial Hospital Presbyterian
Parkview Hospital
Berks Cardiology
Chesapeake General Hospital
Kaiser Foundation Hospital – San Diego
Wellmont Holston Valley
St. Mary’s Hospital/ VA Cardiovascular Specialists
St. Joseph Hospital Wellness Center
Stern Cardiovascular Center
Wake Medical Center
St. Luke’s Hospital, Phoenix
Presbyterian Heart Institute-Dallas
Providence Medical Center
Duke University
Austin Heart P.A.
Baptist Hospital of East Tennessee
Westlake Medical Center
Kaiser Permanente Hawaii
St. Luke’s Episcopal Hospital, Houston
Cardiovascular Inst. of the South
Forsyth Medical Center
VIVA 2007 ( Las Vegas, NV)
September 25th 2007
Ochsner Clinic Foundation
BCVI

47. ACT I: Outcomes Lead In Patients
Event
30 days, N=180
Death, Stroke and MI
1.7% (3/180)
All Stroke and Death
1.7%
Major Stroke and Death
0.0%
Death
All Stroke
Major Stroke
Minor Stroke MI
days, N=157
Ipsilateral Stroke
Updated Source: 2009 IDE Annual Report ACT I Study Sept 2009.
Source: IDE Annual Progress Report ACT I Study Sep 2008
2 minor ipsi strokes within 30 days.

49. Therapy for Carotid Stenosis Conclusions IV
The Future - better definition of patients appropriate for…
Medical Therapy
CEA only
Stenting only
Patients in “gray zone” between revasc or no revasc
Patients who could benefit equally from either CEA or CAS and are appropriate for both